Fluoro^ia.pregnadien-iga,iya,zi.-triol-j,
zq-biones and intermediates in the pro-
duction thereof



United States Patent 34 Claims. (fill. 2 60239.55)

The present invention relates to cyclopentanophenanthrene derivatives and to a process for the production thereof.

More particularly the present invention relates to 60- fiuoro-A -pregnadien-l6a,l7 x,2l-triol-3,20-dione and 6afluoro-A -pregnen-16u,17o,21-triol-3 ,20-dione compounds having an ll-keto or an ll'B-hydroxy group and also having in some instances a 9a-chloro or 9oc-fl11010 substituent. The present invention also relates to 2l-mono esters and 16,21-diesters of these compounds of hydrocarbon carboxylic acids of-less than 12 carbon atoms. All of the compounds just referred to and hereinafter described in detail are active cortical type hormones having a pronounced anti-inflammatory and other effects of this type of hormone, together with less undesirable side reactions such as, for example, sodium retention.

In accordance with the present invention it has been discovered that the novel 6a-fluoro-A -pregnadien-16a, 17a,21-triol-3,20-dione derivatives having an ll-keto or llB-hydroxy and with or without a 9a-chloro or 9a-fluoro substituent may be prepared from the corresponding 6afluoro-cortisone compounds with or without a 9u-chloro or 9u-fluoro-substituent. These compounds are disclosed in US. applications Serial No. 740,550, filed June 9, 1958, now Patent No. 2,934,546, and Serial No. 749,652, filed July 21, 1958, now Patent No. 2,951,840. The aforementioned 6a-fluoro-cortisone compounds are first converted to the corresponding 3,20-bis ketals, the ketals (in form of their Zl-esters) were then dehydrated at Cl6(l7). The Cl6( 17) double bond was then hydroxylated to form the corresponding Got-fluoro-l6u-hydroXy-cortisone compound. To form the llfi-hydroxy derivatives the 3,20-bis ketals of the Gm-flUOIO cortisone compounds are first reduced to the hydrocortisone type compounds. By reaction with selenium dioxide or other conventional dehydrogenation agents the 6a-fluoro-16a-hydroXy-cortisone or hydrocortisone derivatives were converted to the corresponding prednisone or prednisolone derivatives.

Certain of the novel final compounds and cortical hormones of the present invention are illustrated by the following formula:

(ilHzORa In the above formula X represents =0 or Y represents a double bond between C-1 and C-2 or a saturated linkage between 0-1 and C2, R represents by- 3,248,380 Patented Apr. 26, 1966 ice drogen chlorine or fluorine and R and/or R represents hydrogen or a hydrocarbon carboxylic acyl group of less than 12 carbon atoms. R may be noted, however, is an acyl group only when R is also an acyl group. These acyl groups may be saturated or unsaturated, straight or branched chain aliphatic, cyclic or mixed cyclic-aliphatic and may be conventionally substituted as by halogen or methoxy. Typical acyl groups are acetate, propionate, butyrate, cyclopentylpropionate, benzoate, enanthate, etc.

The novel compounds above set forth as well as certain novel intermediates were prepared by a process illustrated in part by the following equation:

reducing I:O\ 0

agent 0 l O I F F l hydrolysis l hydrolysis (I) H2011 ('1 H2O H C O O O osmium osmium tetroxide tetroxide C H; O R 2 ('3 H20 R; O O 0 0 \dehydrogeuation IZ/ dehydrogenation In the above equation X, R, R and R represent the same groups as heretofore set forth.

In practicing the process above outlined 6oc-fiI1OI'O-9otchloro-cortisone is conventionally refluxed with ethylene glycol in the presence of benzene and p-toluenesulfonic acid to form the corresponding 3,20-bis-cycloethyleneketals thereof. The bis-ketals were then conventionally acylated at C-21 to form conventional esters as indicated in the equation. The esters were then reacted with thionyl chloride in pyridine solution to form the corresponding 21-acylate of 6-fiuoro-3,ZO-bis-ethylenedioxy- A -pregnadien-21-ol-1l-one, or its 9OL-fl11OI'O or 90:- chloro analogue. The acyl group was then saponified by reaction with an alkali metal hydroxide under mild con' ditions and the ketal groups hydrolyzed with acid to prepare 6a-tluoro-, 6a-fiuoro-9a-chloroor 6a,9a-difluoro- A -pregnadien-2l-0l3,11,2O-tri0ne. The same compounds having an llfl-hydroxy group were also prepared by reducing the ll-keto group of the last mentioned 3,20- bis-ethylenedioxy derivatives with lithium aluminum hydride. Reaction of A -compounds having either an 11- keto or llfl-hydroxy group with osmium tetroxide under the conditions described by Bernstein et al. (I.A.C.S. 78, 1909 (1956)) gave 6a-fluoro-A -pregnen-16a,17a,21- triol 3,11,20 trione, 6a,9a-difiuoro-A -pregnen-16a,17u, 21-triol-3,11,20-trione and Gzx-flUOl'O-Qoc-ChlOfO-A -pI8g nen-16a,17a,2l-triol-3,11,20-trione, as well as the 115- hydroxy derivatives namely 6oc-flu0rO-, 6a,9ocdifluOIO and 6wfiuoro-9a-chloro-A -pregnen-11[3,16a,17a,21-tetrol- 3,20-dione. The reaction of all of these compounds with selenium dioxide in t-butanol gave the corresponding A -dienes. Preferably this reaction was with the compounds in the form of their 21-monoesters or 16,21-diesters followed by subsequent conventional saponification to form the free dienes.

All of the above compounds upon conventional esterification gave the corresponding 21-mono esters and 16,21-diesters of the type previously set forth. Reaction with a slight excess of acid anhydride gave the 21-mono esters and reaction with an excess of anhydride gave the 16,21-diesters. Mixed esters were formed by first esterifying at C-21 with one acid anhydride and subsequently treating the 21-mono ester with another acid anhydride.

The 16-hydroxy derivatives of the present invention were also obtained by incubating the corresponding 16- unsubstituted compounds with Streptomyccs roseochromogenus as hereinafter set forth in detail.

The following specific examples serve to illustrate but are not intended to limit the present invention.

Example I A mixture of 6 g. of 6a-fiuoro-cortisone, 140 cc. of anhydrous benzene, 48 cc. of ethyleneglycol, distilled over sodium hydroxide, and 0.6 g. of p-toluenesulfonic acid was refluxed for 8 hours with the use of an adapter for the continuous removal of the water formed during the reaction. The cooled mixture was mixed with sodium bicarbonate solution and the organic layer was separated and washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. Crystallization of the residue from acetonehexane yielded the 3,20-bis-cycloethyleneketal of 6afiuoro-cortisone. The pure product was obtained after recrystallization from acetone-hexane.

Similarly there were prepared the 3,20-bis-ketals of 6oc-fitlOfO-9a-ChlOIO-COl'tlSOIlc and of 6u,9a-difiuoro-cortisone.

5 g. of the above crude ketals was dissolved in 30 cc. of pyridine, mixed with 5 cc. of acetic anhydride and kept overnight at room temperature. After pouring into water the product was extracted with methylene dichloride, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue consisted of the 21-acetate of the crude ketal of 6a-fluoro-cortisone or of its analogues further having a halogen atom at C-9a. The pure products were obtained by recrystallization from acetone-hexane.

Example II A solution of 5 g. of the 21-acetate bis-ketal of 6afiuoro cortisone (6-fiuoro-21-acetoxy-3,20-bis-ethylenedioxy-A -pregnen-17a-ol-1l-one) in 50 cc. of pyridine was cooled to 0 C. and mixed under stirring with 3.0 cc. of thionyl chloride. The stirring was continued for 1 hour at 0 C. and then the mixture was poured into ice water and the product was extracted with methylene dichloride, well washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The residue was purified by chromatography, thus furnishing the 21-acetate of 6-fiuoro-3,2O-bis-ethylenedioxy-A pregnadien-Z 1-ol-1 l-one.

5 g. of the above acetate was mixed with 50 cc. of 1% potassium hydroxide in methanol previously cooled to 0 C. and the mixture was stirred at 0 C. under an atmosphere of nitrogen for 1 hour. It was then neutralized with acetic acid and diluted with water. The precipitate was collected, washed with water, dried and purified by crystallization from acetone-hexane, thus giving the pure 6-fluoro-3,20-bis-ethylenedioxy-A -pregnadien- 21-ol-11-one.

A solution of 4 g. of the above compound in 700 cc. of ethanol was treated with cc. of dilute sulfuric acid (8% by volume), refluxed for 40 minutes, cooled and neutralized with solid sodium bicarbonate; the mixture was concentrated to a small volume under reduced pressure and diluted with water. The precipitate was collected by filtration, washed with water, dried and crystallized from acetone-hexane, thus yielding the pure 6afiuoro-A pregnadien-21-ol-3,11,20-trione.

A solution of 3 g. of the above compound in 60 cc. of anhydrous benzene and 2.8 cc. of pyridine was mixed with 3 g. of osmium tetroxide and the mixture was allowed to stand in the dark at room temperature for 4 days; the osmic ester was then decomposed by the addition of 150 cc. of water, 60 cc. of benzene, cc. of methanol, 18 g. of sodium bicarbonate, with stirring for 4 hours. 200 cc. of chloroform was then added and the dark precipitate was filtered and washed with 800 cc. of hot choloroform. The organic layer was separated from the combined filtrates which was then washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was triturated with acetone, thus producing 6afluoro-la-hydroxy-cortisone in crude form (6a-fluoro-A pregnen-16a,17a,21-triol-3,11,20-trione). Concentration of the mother liquors afforded an additional crop. The

analytical sample was obtained by recrystallization from acetone-hexane.

1 g. of 6ix-fiuoro-16u-hydroxy-cortis'one was dissolved in 10 cc. of pyridine, cooled to 0 C. and treated with approximately 0.3 cc. (1.1 mols) of acetic anhydride and the mixture was kept at 10 C. for 2 hours and then poured into water. The product was extracted with ethyl acetate, washed with dilute hydrochloric acid, sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and evaporated under reduced pressure.

Crystallization of the residue from ethyl acetate yielded the 21-acetate of (Set-fluoro-16a-hydroxy-cortisone.

500 mg. of the above acetate was mixed with cc. of anhydrous-t-butanol, 150 mg. of selenium dioxide and 0.05 cc. of pyridine and the mixture was refluxed for 70 hours under an atmosphere of nitrogen. After cooling, the mixture was diluted with 50 cc. of ethyl acetate and filter-ed through Celite, washing the filter with hot ethyl acetate. The combined filtrate and washings were evaporated to dryness under reduced pressure and the residue was triturated withwater. The precipitate was collected by filtration, washed with water, dried and purified by chromatography on 25 g. of washed alumina. Elution with mixtures benzene-ether and with ether, followed by crystallization of the combined crystalline fractions afforded the 21 acetate of 6c: fiuoro 16a hydroxy-prednisone.

Example Ill By the method of Example 11, 6u-fluoro-9u-chloro-cortisone was converted into 6oz fiuoro 90c chloro-16a-hydroxy-cortisone, its 21-acetate and that of 6a-fluoro-9achloro-16a-hydroxy-prednisone.

Example IV Following the method of Example II, 6a,9a-difiuorocortisone was converted into 6a,9a-difluoro-16a-hydroxycortisone, its ZI-acetate and that of 6a,9ot-dlfillOIO-16ot hydroxy-prednisone.

Example 'V Asolution of 5 g. of 6-fl'uoro-3,ZO-bis-et-hylenedioxy- A -pr-egnadien-2l-ol-ll-one, prepared as described in Example II, in 150 cc. of anhydrous tetrahydrofurane was slowly added to a mechanically stirred suspension of 1.5 g. of lithium aluminum hydride in 100 cc. of anhydrous tetrahydrofurane and the mixture was refluxed for minutes. The excess of anhydride was decomposed by the addition of a few drops of acetone and then 15 cc. of saturated aqueous sodium sulfate solution was added, followed by the addition of anhydrous sodium sulfate. 7 The inorganic salts were removed by filtration and the solution was evaporated to dryness. Crystallization of the residue from acetone-ether yielded 6-fiuoro-3,20-bis-ethylenedioxy-A -pregnadien-l1B,21-diol. I

In another experiment the above compound was obtained from the 21-acetate of 6-fiuoro-3,20-bis-ethylenedioxy-A -pregnadien-2l-ol 11- one, since the reaction with the hydride causes the simultaneous saponification of the acetoxyl group at C-Zl.

The ketal groups of the above. compound were then hydrolyzed following the method described in Example 11, to give 6a-fluoro-A -pregnadien-11fi,21-diol-3,20-dione, which was in turn subjected to the treatment with osmium tetroxide, as described in that example, to produce 6oc-fll10I'O-16oc-hYdlOXY-hYdTOCOIliSOHG.

There was then prepared the 21-acetate of 6a-fluoro- 16a-hydroxy-hydrocortisone, and then the 21-acetate of 6a-fluoro-16a-hydroxy-prednisolone, following exactly the methods of acetylation and dehydrogenation as applied to 6a-fluoro-16a-hydroxy-cortisone.

Example Vl By the method of the previous example, the diketals having the additional halogen substituent at C-9oc, described in Examples II, III and IV, were convertd into the following compounds: 6u-fiuoro-9a-chloro 16a hydroxy-hydrocortisone, 6u,9tx-difluoro-16a-hydroxy-hydrocortisone, their 21-acetates, as well as the 21-acetates of 6oc-fll10lO-9ot-Chl0l0-IGu-hYdIOXY-PI'GdHISOlOI'lfi and of 60a, 9a-difluoro-16u-hydroxy-prednisolone.

Example VII In other experiments, instead of using 1.1 molar equiva lents ofv acetic anhydride for the acetylation of 6a-fiuoro- 16a-hydroxy-cortisone, in accordance with Example II,

there were used approximately 3 mols of the reagent and the mixture was allowed to react overnight at room temperature. There was thus obtained the 16,2l-diacetate of 6a-fluoro-16a-hydroxy-cortisone, and dehydrogenation of the latter with selenium dioxide aiforded the 16,21-diacetate of 6a-fluoro-l6a-hydroxy-prednisone.

Example VIII A mixture of 1 g. of the 21-acetate of 611,9oc-difll101'0- 16a-hydroxy-hydrocortisone, prepared in accordance with Example VI, 10 cc. of pyridine and 1 cc. of propionic anhydride was kept overnight at room temperature, poured into water 0nd extracted with methylene dichloride. The extract was washed with dilute hydrochloric acid, 5% sodium carbonate solution and finally with water, dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization of the residue furnished the 16 propionate 21 acetate of ,9m difluoro 16ahydroxy-hydrocortisone.

Example IX 1 g. of the 2l-acetate of 60c-fll101'0-IGa-hYdIOXY-COrtisone, obtained in accordance with Example III, was suspended in 10 cc. of methanol, cooled to 0 C. and treated with a solution of sodium methoxide prepared by dissolving 60 mg. of sodium metal in 5 cc. of anhydrous methanol. The mixture was stirred for 1 hour at 0 C. under an atmosphere of nitrogen, neutralized with acetic acid and diluted with water. The precipitate formed was collected, washed with water, dried and recrystallized. There was thus obtained the free 6a-fluoro-16u-hydroxycortisone.

Example X By the method of'the previous example, there were saponified the esterified groups at C-21 or at 0-16 and C21, respectively, of all of the 6tx-fiuoro and 6a-fiuoro- 9a-halo derivatives of 16a-hydroxy-cortisone, of 16a-hydroxy-hydrocortisone, of IGa-hydroxy-prednisone and of 16a-hydroxy-prednisolone described in the prior examples, thus producing the corresponding free triols and tetrols.

Example XI All of the free alcohols obtained in accordance with the method of the previous example were esterified following the methods of esterification described in Examples II, VII and VIII.

The reaction with 1.1 molar equivalents of an anhydride of a hydrocarbon carboxylic acid of less than 12 carbon atoms gave the respective 21-esters, while the reaction with an excess of the anhydride produced their 16,21-diesters. There were specifically prepared in this conventional way in addition to the acetates and propionates previously described the 16,21-dibenzoates and dicyclopentylpropionates and the 21-monobenzoates and 21-monocyclopentylpropionates.

Example XII A culture of Streptomyces roseochromogenus A.T.T.C. No. 3347 was prepared in an inclined agar medium containing 1% of glucose and 1% 'of yeast extract. 1 cc. of a suspension of this culture was then used to innoculate each one of a series of 250 cc. flasks containing 50 cc. of a sterilized aqueous medium of 2% peptone and 5% corn syrup; the mixtures were then incubated in a shaking machine at 28 C. under aeration for a period of 24- 48 hours. There was thus a vegetating growing culture of Streptomyces roseochromogenus Which was used for the subsequent incubation of the steroid.

10 g. of 6u-fluoro-cortisone was added to each 50 cc. of the vegetating culture of Streptomyces roseochromogenus, obtained as described above. The mixture was stirred for 48-72 hours with aeration and then extracted several times with methylene dichloride. The extract was washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure.

The residue was purified by chromatography on silica, thus giving 600-fluoro-la-hydroxy-cortisone, identical with that previously obtained.

Example XIII of such cortical hormones.

We claim: 1. A compound of the following formula:

CHZOR:

wherein X is selected from the group consisting of and H Y is selected from the group consisting of a double bond between C-1 and C2 and a saturated linkage between C1 and C-2, R is hydrogen when R is hydrogen and R isselected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms when R is a hydrocarbon carboxylic acyl group of less than 12 carbon atoms, and R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms and R is selected from the group consisting of hydrogen, fluorine and chlorine.

2. 60 fluoro A pregnen 11[3,160t,170t,21 tetrol- 3,20-dione.

3. The 21-monoesters of hydrocarbon carboxylic acids of less than 12 carbon atoms of 60t-fluoro-A -pregnen- 11B,160t,170t,21-tetrol-3 ,20-dione.

4. 60:,90; difluoro A pregnen 1 3,20-dione.

5. The 21-monoesters of hydrocarbon carboxylic acids of less than 12 carbon atoms of 60t,90t-difluoro-A -pregnen- 11fi,160t,1700,21-tetrol-3,20-dione.

6. The 16,21-diesters of hydrocarbon carboxylic acids of less than 12 carbon atoms of 60t,90t-difluoro-A -pregnen- 11 8,160t,17a,21-tetrol-3 ,20-dione.

7. 600 fluoro 90 chloro A pregnen 11,8,160t,170t, 21-tetrol-3,20-dione.

8. The 21-monoesters of hydrocarbon carboxylic acids of less than 12 carbon atoms of 60t-fluoro-90t-chloro-A pregnen-l 1/8,160t,170t,21-tetrol-3 ,20-dione.

9. The 16,21-diesters of hydrocarbon carboxylic acids of less than 12 carbon atoms of 60t-fluoro-900-ehloro-A pregnen-l1B,160,170t,2l-tetrol-3,20-dione.

10. 6a fluoro A pregnadien 11fi,1600,170t,21- tetrol-3,20-dione.

11, The 21-monoesters of hydrocarbon carboxylic acids of less than 12 carbon atoms of 6u-fluoro-A -pregnadien- 11B,160:,1700,21-tetrol-3,20-dione.

12. 600,9a difluoro 4 )i-pregnadien 11fi,160t,1700,21- 1etrol-3,20-dione.

1p,1600,170t,21-tetrol- 1 13. The 2l-monoesters of hydrocarbon carboxylic acids of less than 12 carbon atoms of 600,90t-difiuoro-A -pregnadien-l16,1600,17a,21-tetrol-3,20-dione.

14. The 16,21-diesters of hydrocarbon carboxylic acids of less than 12 carbon atoms of 60t,900-difiuoro-A -pregnadien-l113,160t,17a,2l-tetrol-3,20-dione.

15. 60 fluoro c chloro A pregnadien 11,3, 16a,1700,21-tetrol-3,2O-dione.

16. The 21-monoesters of hydrocarbon 'carboxylic acids of less than 12 carbon atoms of 60; flUOX'O-9OL-Ch1OI'O-A pregnadien-l1,8,16a,17a,21-tetrol-3,20-dione.

17. The 16,21-diesters of hydrocarbon carboxylic acids of less than 12 carbon atoms of 6OL-fl O1'O-9lZ-ChlOIO-A pregnadien-l1,8,160t,17a,21-tetrol-3,20-dione.

18. 60: fluoro 16o,17a,21 trihydroxy 1,4-pregnadiene-3,11,20-trione.

19. 60:,900 difluoro 1606,170L,21 trihydroxy 1,4- pregnadiene-3,11,20-trione.

20. 600 fluoro 11p,160t,170 ,21 tetrahydroxy 1,4- pregnadiene-3,20-dione 16,21-diacetate.

21. 60,900 difluoro 1lfi,1600,170t,21 tetrahydroxy- 1,4-pregnadiene-3,20-dione 16,21-diacetate.

22. 600 fluoro 16a,l70t,21-trihydroxy 1,4-pregnadiene-3,11,20-trione 16,21-diacetate.

. 23. 600,90; difluoro 1600,170t,21-trihydroxy 1,4 pregnadiene-3,11,20-trione 16,21-diacetate.

24. 6a fluoro 16a,170t,21-trihydroxy 4 pregnene- 3,11,20-trione.

25. 600,90: difluoro L,170t,21 trihydroxy 4 pregnene-3 ,11,20-trione.

26. 60c fluoro 11/3,160t,170t,21 tetrahydroxy-4-pregnene-3,20-dione 16,21-diacetate.

27. 60,900 difluoro 11,13,16oc,17a,21 tetrahydroxy 4- pregnene-3,20-dione 16,21-diacetate.

28. 600 fluoro 160t,1700,21 trihydroxy 4 pregnene- 3,11,20-trione 16,2l-diacetate.

29. 60:,900 difluoro 16a,170t,21 trihydroxy 4 pregnene-3,11,20-trione 16,21-diacetate.

30. A 16-0xygenated pregnadiene of the formula X i TOR ---0H i Ton wherein Y is selected from the group consisting of hydrogen and fluorine, X is selected from the group consisting of the carbonyl radical and the B-hydroxymethylene radi- 9 10 cal, and R is the same member selected from the group 34. A compound of the formula: consisting of hydrogen and the acyl radical of a hydrocarbon carboxylic acid containing less than 12 carbon 3111011 atoms. :0

32. 6 fluoro 90c Z 3,20 bis ethylenedioxy A 5 A I pregnene-17a,21-dio1-1l-one, wherein Z is selected from X the group consisting of hydrogen, fluorine and chlorine. i 33. A compound of the formula: I

CHZOH i/ C F i I v 0 wherein X is selected from the group consisting of =0 and and R is selected from the group consisting of hydrogen,

20 l: fluorine and chlorine.

References Cited by the Examiner UNITED STATES PATENTS wherein X is selected from the group consisting of :0

. 2,777,864 1/1957 Bernstein et al. 260397.45

and 2,838,497 6/1958 Spero et a1 260239.55 2,838,498 6/1958 Magerlein et al. 260239.55

2,838,546 6/1958 Magerlein et al. 260397.45

2,838,548 6/1958 Magerlein et a1. 260397.45

LEWIS GOTTS, Primary Examiner.

and R is selected from the group consisting of hydrogen, JULIUS FROME, B. E. LANHAM, MORRIS LIEB- fluorine and chlorine. MAN, Examiners. 

33. A COMPOUND OF THE FORMUL: 